Project Summary/Abstract Primary open angle glaucoma (POAG) is an optic neuropathy with a characteristic pattern of visual field loss and optic disc cupping due to progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is an important risk factor for POAG, and artificially raising IOP is very effective at inducing glaucoma in animal models. However, the relationship between IOP and RGC death is unclear since some patients with normal IOP develop glaucoma while others with elevated IOP do not. Our group made a breakthrough discovery that a mutation in ADAMTS10 causes POAG in Beagle dogs. This finding was independently validated and expanded by identification of another mutation in ADAMTS10 causing POAG in Norwegian Elkhound dogs and 3 other mutations in a closely-related gene, ADAMTS17, in 3 other dog breeds. Relevant to human glaucoma, an ADAMTS8 locus has been identified associated with vertical cup -disc ratio. These findings suggest that mutations in ADAMTS genes cause POAG. In humans, null mutations of ADAMTS10 cause Weill-Marchesani syndrome, a disease associated with defective microfibrils and characterized by short skeletal features, lens dislocation and glaucoma. ADAMTS10 is a microfibril-associated protein that plays a role in microfibril structure and function. Microfibrils are components of the extracellular matrix that are key regulators of Transforming Growth Factor Beta (TGF?) signaling and contribute to mechanotransduction involving ligand-independent activation of the Angiotensin II Type I Receptor (AT1R). Hyper-activation of TGF? signaling and altered mechanotransduction are key pathogenic mechanisms for both microfibril deficiencies and POAG. Identification of a microfibril-associated gene as causative for POAG led us to formulate our central hypothesis that ADAMTS10 mutations cause glaucoma by disrupting microfibril structure and function. Establishing microfibril defects as a disease mechanism would suggest that treatments effective in other diseases caused by microfibril deficiencies may be applied to POAG. AT1R blockers (ARBs) are effective in treating diseases associated with microfibril deficiencies and they have been considered as potential glaucoma treatments owing to their IOP-lowering and neuroprotective effects. Based on our microfibril hypothesis, we will test the efficacy of ARBs in treating glaucoma caused by ADAMTS10 mutations. For this project, we will use mouse and zebrafish lines homozygous for glaucoma-causing mutations in Adamts10. In Specific Aim 1, we will test the fundamental hypothesis that microfibril deficiencies cause POAG. In Specific Aim 2, we will investigate molecular mechanisms of POAG caused by ADAMTS10 mutations. In Specific Aim 3, we will test the efficacy of ARBs in treating or preventing glaucoma phenotypes caused by ADAMTS10 mutations.